Abstract. Conventional asthma therapies are often ineffective for patients with severe and exacerbation-prone asthma, conditions accounting for up to half of the morbidity, mortality and economic burden of asthma. We and others have identified subsets of these patients (endotypes) for whom there are treatable mechanisms contributing to airflow obstruction. The investigators in our proposal have collaborated for the nearly two decades to define the biology of severe and exacerbation prone endotypes. We have also developed biomarkers that will likely predict response to therapy targeted specifically to each endotype. Many of these biomarker/endotype pairs may ultimately be studied by the PrecISE consortium. Here, we have focused on treating three of these that our data suggests will overlap minimally with one another and will be safe, effective and cost-saving. These are 1) urinary bromotyrosine to identify the 70% of eosinophilic patients for whom ant-IL5 will be effective; 2) serum superoxide dismutase activity to identify patients who will respond to oral Coenzyme Q; and 3) serum dehydroepiandrosterone (DHEA) sulfate to identify patients who will respond to oral DHEA. We propose to use an adaptive trial design to test and improve the predictive and response biomarkers for all three endotypes. These studies fit into the framework of a sequential multiple assignment randomized trial (SMART) or equivalent, where each patient will start an initial treatment based on the baseline biomarker profile, followed by re- assignment of non-responders to other treatments at each subsequent stage (Figure 1). Our key objectives are summarized by three Aims. Precision treatment Aim 1. Test the hypothesis that Anti-Interleukin 5 (Mepolizumab) will decrease eosinophil activation as measured by urine bromotyrosine (BrTyr) in the Th2-high severe asthmatic patient and consequently improve lung function and asthma control. Precision treatment Aim 2. Test the hypothesis that CoQ supplementation will restore the antioxidant capacity and reducing-oxidizing balance in severe asthmatic patients with decreased serum SOD activity, and will consequently improve lung function and asthma control. Precision treatment Aim 3. Test the hypothesis that DHEA supplementation will improve FEV1, asthma control and DHEAS levels in older women and younger male adolescents with SA and EPA .To accomplish these Aims, we plan to participate in the PrecISE network, enrolling 100 subjects with severe and/or exacerbation prone asthma. These will include both children (12-18) and adults, reflecting our longstanding Pediatric/adult collaboration. We have research infrastructures at our three sites that have already collaborated for over a decade and have extensive experience both with NIH and industry-based trails.